上皮间质转化（EMT）与肿瘤细胞侵袭转移关系密切，Wnt/β-catenin被认为是EMT效应中最重要的信号通路，但迄今对EMT在结直肠癌转移中的调控机制仍不够清楚。我们前期工作中在30例配对的大肠癌转移灶中发现Wnt/β-catenin信号通路中的关键分子NLK表达比原发灶显著升高，细胞实验证实NLK基因沉默后其生长显著减缓、克隆形成和转移能力降低，过表达该基因则表型相反。同时NLK能够介导细胞形态变化和EMT标志蛋白的表达改变。此外，我们在裸鼠转移模型中验证了下调NLK表达能够显著抑制结直肠癌肝转移。在此基础上，本项目拟进一步从分子、细胞、组织、动物水平多层次研究NLK与结直肠癌转移的功能和相关机制，深入探讨NLK基因调控EMT的相关信号通路和下游作用分子。并通过大样本组织芯片回顾性研究阐释NLK表达与结直肠癌临床病理与转移复发的相关性，明确其临床意义，为大肠癌肝转移提供新的治疗靶点。

Epithelial-mesenchymal transitions (EMT) are implicated in the conversion of early stage tumors into invasive malignancies. The Wnt/β-catenin signaling pathway plays a pivotal role in EMT of human cancers. However, the regulatory mechanism of EMT in colorectal cancer (CRC) metastasis is still not yet clear. From previous results of 30 paired primary CRC and metastatic lesions, we found that the expression of nemo-like kinase (NLK) protein was significantly higher in the metastatic CRC lesions than in primary CRC tissues. Furthermore, we found that knockdown of NLK significantly hampered the growth and colony formatting ability of CRC cells, and inhibited tumor metastasis while overexpression of NLK changed the phenotype reversely. More importantly, down-regulation of NLK altered the cell morphology and expression of EMT markers. Theses function of NLK could be verified in migration model of nude mice. Based on our preliminary work, we will investigate the effect of NLK on the metastasis of CRC and the regulatory role of NLK-mediated Wnt signaling pathway in EMT process in CRC progression in the present study. Moreover, we will further explore the molecular mechanism by which NLK regulates the metastasis and EMT in CRC. Finally, we will perform a retrospective study on a cohort of patients with CRC to assess the correlation between NLK expression and the metastasis and recurrence of CRC and its clinical significance. Overall, this study could provide a new molecular target for the treatment of colorectal cancer liver metastases.